Pharmacometabolomic Assessments of Atenolol and Hydrochlorothiazide Treatment Reveal Novel Drug Response Phenotypes.

Achieving hypertension (HTN) control and mitigating the adverse health effects associated with HTN continues to be a global challenge. Some individuals respond poorly to current HTN therapies, and mechanisms for response variation remain poorly understood. We used a nontargeted metabolomics approach (gas chromatography time-of-flight/mass spectrometry gas chromatography time-of-flight/mass spectrometry) measuring 489 metabolites to characterize metabolite signatures associated with treatment response to anti-HTN drugs, atenolol (ATEN), and hydrochlorothiazide (HCTZ), in white and black participants with uncomplicated HTN enrolled in the Pharmacogenomic Evaluation of Antihypertensive Responses study. Metabolite profiles were significantly different between races, and metabolite responses associated with home diastolic blood pressure (HDBP) response were identified. Metabolite pathway analyses identified gluconeogenesis, plasmalogen synthesis, and tryptophan metabolism increases in white participants treated with HCTZ (P < 0.05). Furthermore, we developed predictive models from metabolite signatures of HDBP treatment response (P < 1 × 10(-5)). As part of a quantitative systems pharmacology approach, the metabolites identified herein may serve as biomarkers for improving treatment decisions and elucidating mechanisms driving HTN treatment responses.

[Liberalisation of preoperative fasting guidelines: effects on patient comfort and clinical practicability during elective laparoscopic surgery of the lower abdomen]. / Liberalisierte präoperative Flüssigkeitskarenz: Patientenbefinden und klinische Praktikabilität bei elektiven laparoskopischen Eingriffen im Unterbauch.

INTRODUCTION: In this study, the recently liberalised national guidelines for preoperative fasting were evaluated from the view point of the patients and according to their clinical usability. PATIENTS AND METHODS: Patients undergoing elective laparoscopic gynaecological surgery were randomised into two groups. Patients in the long-time NPO-group (LTNPO-group) had nothing per mouth after midnight whereas patients in the short-time NPO-group (STNPO-group) did not receive any oral nutrition after midnight but were allowed an unlimited intake of Pfrimmer Nutricia preOP up to 2 hours before scheduled surgery. Patients were asked to assess the incidence of 12 symptoms of perioperative discomfort prior to and 4-6 hours after surgery using a standardised questionnaire. Gastric fluid volume, vital signs during the induction period of anaesthesia and the actual duration of fasting were registered and compared. RESULTS: 42 patients were included into the study (LTNPO-group: n = 23, STNPO-group: n = 19). The actual duration of fasting for solid nutritition was 11.3 h in the LTNPO-group and 10.9 h in the STNPO-group, respectively. The time of fasting for fluids was in the STNPO-group significantly shorter (4.5 h) compared to the LTNPO-group (11.3 h). The patients of the STNPO-group reported preoperatively a significant lower incidence of "feeling cold" and pre- and postoperatively of "thirst / having a dry mouth". No significant differences were reported between the groups with respect to heart rate, blood pressure, gastric volume, need of vasopressors and infusion requirements. DISCUSSION: The liberation of the national guidelines for preoperative fluid administration with unlimited intake of a carbohydrate drink offers the benefit of a significantly lower incidence of the preoperative item "feeling cold" and of the pre- and postoperative item "thirst / having a dry mouth". However, in daily clinical practice the length of fasting for fluids was conspicuously longer than that postulated by the new recommendations.

[Patients with ornithine transcarbamylase deficiency. Anaesthesiological and intensive care management]. / Der Patient mit Ornithintranscarbamylasemangel. Anästhesiologisches und intensivmedizinisches Management.

Ornithine transcarbamylase deficiency (OTCD) is the most common inborn urea cycle disorder. Patients with OTCD are at risk of acute metabolic decompensation with hyperammonemia and subsequent encephalopathy, coma and death. Symptoms may be triggered by infections, drugs and stress, evoked by trauma, pain, fear, surgery and anaesthesia or by episodes of protein catabolism, i.e. fasting-induced, post partum or during gastrointestinal bleeding. Several specific considerations must be made for anaesthetic and intensive care management in patients with this disease in order to avoid metabolic decompensation. We report the intensive care management of the first manifestation of late-onset OTCD in a 16-year-old girl and a course of inconspicuous general anaesthesia with midazolam, s-ketamine, fentanyl and isoflurane in a 22-year-old girl with known OTCD.

[Procalcitonin as a marker for severe sepsis in an immunosuppressed patient]. / Procalcitonin als Marker der schweren Sepsis bei einer immunsupprimierten Patientin.

A 22 year old female was admitted to the emergency department with high fever up to 41,5 degrees C, tachycardia, and arterial hypotension. Clinically, she presented with bilateral pulmonary coarse crackles. Diagnosis on admission was pneumonia with septic shock. Intriguingly, procalcitonin (PCT) was increased early, reaching up to 435 ng/mL, while C-reactive protein levels were only moderately increased, with several days delay. The sepsis was originated from a multi-resistant pseudomonas aeruginosa pneumonia. Remarkably, the course of PCT levels reflected the severity of septic shock in that it paralleled noradrenaline demand. Ten months previously, the patient had been diagnosed with acute disseminated brainstem encephalitis (ADEM), and had received two cycles of intravenous cyclophosphamide. Our case illustrates that PCT is an early marker for sepsis and it indicates that PCT may also be a valuable marker for the severity of sepsis in immunosuppressed patients.

Early increase of procalcitonin after cardiovascular surgery in patients with postoperative complications.

OBJECTIVE: Type and frequency of postoperative abnormalities were registered after cardiovascular surgery to evaluate the aetiology and diagnostic value of increased concentrations of procalcitonin (PCT) and C-reactive protein (CRP) during the early postoperative period. DESIGN: Prospective, observational study. PATIENTS: Two hundred and eight patients undergoing coronary artery bypass grafting or valve replacement requiring cardiopulmonary bypass were monitored for 7 days postoperatively for various types of infectious or non-infectious complications. Plasma PCT and CRP levels were measured on day 1 and day 2 after surgery and, when increased, until day 7. RESULTS: More patients with PCT above 2 ng/ml on day 1 or 2 (n=55) had postoperative abnormalities (95%) than patients with lower PCT (59%). Specifically, the incidence of three or more criteria of the "systemic inflammatory response syndrome" was 45% versus 4% (area under the curve of the receiver operating characteristic 0.866); positive inotropic support was needed in 65% versus 9% (0.870); respiratory insufficiency (PaO(2)/FIO(2)<200) 38% versus 12% (0.704); proven and suspected bacterial infection 9% versus 1% (0.900) and 24% versus 1% (0.897), respectively. For CRP, the respective areas under the curve were all below 0.63, while all patients had elevated CRP levels, whether they had a complication or not. CONCLUSIONS: Elevated PCT, but not CRP, correlates with evidence of systemic inflammation and other complications early postoperatively after cardiac surgery. Although the PCT levels do not rise as quickly as the criteria of the systemic inflammatory response syndrome appear, they do reflect systemic inflammation. Early identification and quantification of a systemic inflammatory response may help reduce postoperative complications.

Statistical cost-effectiveness analysis of two treatments based on net health benefits.

Statistical methods for cost-effectiveness analysis (CEA) for two treatments that mimic the deterministic optimal rules of CEA are presented. In these rules the objective is to determine the treatment with the maximal effectiveness whose unit cost is less than an amount, lambda, that a decision-maker is willing to pay (WTP). This is accomplished by identifying the treatment with the largest positive net health benefit (NHB), which is a function of lambda, while controlling the familywise error rate both when the WTP value is given and when it is unspecified. Fieller's theorem is used to determine a region of WTP values where the NHBs of the treatments are not distinguishable. For each lambda outside of the confidence region, the larger treatment is identified. A newly developed one-tailed analogue of Fieller's theorem is used to determine the WTP values where a treatment's NHB is positive. The situation in which both treatments are experimental is distinguished from the case where one of the treatments is usual care. The one-tailed confidence region is used in the latter case to obtain the lambda values where the NHBs are not different, and determining the region of positivity of the NHBs may be unnecessary. An example is presented in which the cost-effectiveness of two antipsychotic treatments is evaluated.

[Leukocytopenia as an incidental finding. Finding the etiology]. / Zufallsbefund Leukozytopenie. So finden Sie die Ursache.

Any leukopenia of less than 1000/microliter poses an acute threat to life, and mandates an immediate search for the underlying cause. An extensive history-taking (use of drugs? visits abroad? previous illnesses?) and physical examination (splenomegaly? exanthema? signs of hemorrhage?) are mandatory. In addition to a manual differential blood count, bone marrow aspiration for cytological and histological evaluation must be requested. In this overview, the major differential diagnoses, such as allergic agranulocytosis, leukemia, pernicious illnesses (e.g. malaria), hypersplenic syndrome and a number of infectious diseases are discussed.

The plasma elimination rate and urinary secretion of procalcitonin in patients with normal and impaired renal function.

BACKGROUND AND OBJECTIVE: The amount of procalcitonin eliminated in the urine and the plasma disappearance rate of procalcitonin were evaluated in patients with normal and impaired renal function, because patients with sepsis are a main target group for procalcitonin measurement, and these patients often develop renal dysfunction. METHODS: Elimination of procalcitonin in the urine (microgram 12 h-1) was measured in 76 patients. In another 67 patients, the 50% plasma disappearance rate (t1/2, h) was evaluated 48 h after peak concentrations (procalcitonin > 2 micrograms L-1). Renal function was assessed by creatinine clearance. RESULTS: Procalcitonin elimination in the urine was significantly reduced in patients with severe renal dysfunction. However, the plasma disappearance rate correlated only weakly with renal dysfunction (Spearman's rank correlation R = -0.36, P = 0.004, regression t1/2 = 49.87-0.15 creatinine clearance). The 25% quartile and median were 25.2 h and 30.0 h in patients with normal renal function, and 36.3 h and 44.7 h in patients with severely impaired renal function (creatinine clearance < 30 mL min-1). CONCLUSIONS: Renal elimination of procalcitonin is not a major mechanism for procalcitonin removal from the plasma. Although the plasma disappearance rate may be prolonged up to 30-50% in some patients with renal dysfunction, clinical diagnostic decisions may not be severely influenced by this moderate prolongation of procalcitonin elimination. We conclude that procalcitonin can be used diagnostically in patients with renal failure as well as in those with normal renal function.

Plasma concentrations and clearance of procalcitonin during continuous veno-venous hemofiltration in septic patients.

We determined the elimination characteristics of procalcitonin (PCT) during continuous veno-venous hemofiltration (CVVHF) and the resulting effect on PCT plasma levels. A prospective study was conducted in patients with sepsis and acute oliguric renal failure, treated with CVVHF using a polysulfone membrane (Baxter Renaflo II PSHF 1200). Patients had sepsis and PCT plasma levels > 4 ng ml(-1) (n = 26). PCT was measured in the pre- and post-filter plasma and the ultrafiltrate at 0, 5, 10, and 15 min and 1, 2, 4, 6, 12, and 24 h after setup of CVVHF. PCT sieving coefficient was 0.24. Elimination of PCT, however, depended on the duration of filtration, because filter adsorption was the main mechanism of PCT clearance during the first hour of hemofiltration, finally increasing to a clearance of PCT into the ultrafiltrate of 2.8-5.5 mL/min after 2 h. PCT plasma levels were not significantly altered during CVVHF (96% of the initial concentration after 24 h, P = 0.72). Similar to what has been observed with cytokines and other proteins of a comparable molecular weight, PCT is removed from the plasma during CVVHF, but plasma PCT levels are unchanged. Thus, PCT can be used as a diagnostic parameter even in patients with acute renal failure undergoing CVVHF.

Elimination of procalcitonin and plasma concentrations during continuous veno-venous haemodiafiltration in septic patients.

The elimination of procalcitonin and the course of plasma concentrations during continuous veno-venous haemodiafiltration were measured in patients with sepsis or multiple organ dysfunction syndrome, because these patients are a main target group for the measurement of procalcitonin and often require renal replacement therapy. Procalcitonin was measured in the prefilter plasma and the filtrate at 5 min, 15 min and 1, 2, 4, 6, 12, 24 h after set-up of continuous veno-venous haemodiafiltration. In a prospective study, 19 patients with plasma levels of procalcitonin > 3 ng mL-1 and acute oliguric renal failure treated with continuous veno-venous haemodiafiltration using a polysulphone membrane, were evaluated for the study of clearance. Twenty-one control patients (procalcitonin < 2 ng mL-1) were studied to determine whether filtration itself induced a procalcitonin response. No interventions were required. In patients with low procalcitonin concentrations (procalcitonin < 2 ng mL-1) continuous veno-venous haemodiafiltration did not cause a rise in procalcitonin. In patients with increased procalcitonin plasma concentrations (> 3 ng mL-1), the protein was removed through the polysulphone membrane, with a final clearance of 4 mL min-1 after the initial adsorption period (clearance 0.4-0.9 mL min-1 during the first hour of continuous veno-venous haemodiafiltration). Thus, on the average, approximately 10% of plasma concentrations were measurable in the filtrate ultimately. However, procalcitonin plasma levels were not significantly altered during continuous veno-venous haemodiafiltration (86% of the initial concentration after 24 h). Although procalcitonin is removed from the plasma during continuous veno-venous haemodiafiltration in measurable amounts plasma procalcitonin concentrations did not change significantly during haemodiafiltration. Procalcitonin thus can also be used as a diagnostic parameter in patients undergoing continuous veno-venous haemodiafiltration.

Influence of pyrrolidine dithiocarbamate on the inflammatory response in macrophages and mouse endotoxin shock.

To analyze the immunomodulatory effect of pyrrolidine dithiocarbamate (PDTC) on the endotoxin (LPS) stimulated inflammatory response, we measured the LPS-stimulated cytokine and NO production in murine peritoneal macrophages, J774A.1 cells and human whole blood in the presence of PDTC (60 microM). PDTC significantly inhibited the production of nitrite, IL-1beta and IL-6 in these cells. TNFalpha release was stimulated in murine cells, but suppressed in human whole blood. We further investigated the influence of PDTC on mortality and cytokine release in mouse endotoxin shock. PDTC was i.p. injected 30 min prior to the induction of endotoxin shock in female NMRI-mice and survival was significantly improved as compared to controls (48% vs 20%, n=25 per group). Plasma concentrations of TNFalpha were slightly augmented while IL-6 levels were decreased in PDTC-treated animals as compared to controls, however, without reaching significance. We conclude that PDTC is a potent immunomodulatory substance that modulates the inflammatory response in vitro and reduces mortality in mouse endotoxin shock. The pathophysiological mechanisms of the protective effect of PDTC in vivo, however, appears to be pluripotent, comprising both antioxidative properties and the inhibition of NF-kB.

Clinical experiences with a new semi-quantitative solid phase immunoassay for rapid measurement of procalcitonin.

A self-developing solid-phase immunoassay (B.R.A.H.M.S. PCT-Q, B.R.A.H.M.S.-Diagnostica GmbH, Hennigsdorf, Germany) has recently become available for the semi-quantitative and rapid measurement of procalcitonin (PCT). In this study we examined the validity of this assay at daily clinical routine conditions at five different hospitals in a prospective study. After development of the assay (200 microl plasma, 30 minutes incubation), PCT levels were categorized into four groups (< 0.5 microg/l; > or = 0.5-< 2 microg/l; > or = 2-< 10 microg/l; > or = 10 microg/l) according to the provided reference scale. Samples from patients with suspected elevation of PCT of different etiology (n=237) were read by various analyzers and compared with the results of the Lumitest PCT (B.R.A.H.M.S.-Diagnostica GmbH, Hennigsdorf, Germany). A total of 74.7% of measurements were categorized according to the results of the LumitestPCT, 24.5% were read within the next lower or higher category. Using a +/- 10% range at the reference concentrations (20% at 0.5 microg/l), 82.7% of samples were correctly categorized and 16.4% within the next categories. Using a cut-off value of 2.0 microg/l, 92.0% (94.1% for +/- 10%) of the results were correctly categorized. The semi-quantitative solid phase immunoassay allows a rapid, simple and semi-quantitative measurement of plasma PCT. The validity of the test results and its ease of use are sufficient to support acute diagnostic decisions. However, for the follow-up of PCT concentrations and routine daily measurements, the quantitative luminometric assay should be preferred, when available.

Modulation of the ceramide level, a novel therapeutic concept?

The sphingomyelin (SM) pathway is an ubiquitous and evolutionarily conserved signaling system in which ceramide (CA), generated from SM by the action of various isoforms of sphingomyelinases (SMases) functions as an important second messenger. Recent evidence suggests that branching pathways of sphingolipid metabolism mediate either apoptotic or mitogenic responses depending on cell type and the nature of the stimulus. Events involving SM metabolites and CA in particular include proliferation, differentiation and growth arrest as well as the induction of apoptosis. An improved understanding of SMase-dependent signaling may afford relevant insights into the pathogenesis of diseases and provide novel strategies and selective targets for a therapeutic intervention e.g. in cancer, cardiovascular and neurodegenerative diseases, HIV and septic shock. This article briefly summarizes the role of SMases in signaling pathways, its potential contribution in the development and maintenance of various pathobiological states and analyzes the perspective of a potentially isotype-specifc inhibition of SMases as a novel therapeutic concept.

The natural elimination rate of procalcitonin in patients with normal and impaired renal function.

OBJECTIVE: Procalcitonin (PCT) plasma concentrations and its kinetic can be used as a diagnostic tool in critically ill patients and patients with sepsis. Since renal dysfunction is a frequent complication in these patients, and PCT is a protein with a low molecular weight, we have measured the half-life time of PCT after peak concentrations in patients with normal and impaired renal function. We also have analyzed the influence of patients age and gender on PCT elimination kinetics. DESIGN: Prospective clinical study. Renal dysfunction was assessed by plasma creatinine. The half-life time of PCT was evaluated 24 and 48 h after acute induction of PCT, when the focus of PCT induction has rapidly been eliminated. SETTING: Intensive care unit of our University hospital, a tertiary health care institution. PATIENTS: 69 patients were included into the study. INTERVENTIONS: None. MEASUREMENTS AND RESULTS: The half-life-time of PCT was not significantly altered during renal dysfunction (26.1-33.1 h, 25-50 percentiles, creatinine clearance < 30 ml/min) when compared with normal renal function (22.3-28.9 h). It neither correlated with creatinine clearance (p=0.14), nor age (p=0.99) or gender (p=0.90, Pearson product-moment correlation). CONCLUSIONS: The data of the present study demonstrate that assessment of PCT kinetic can also be used for diagnostic and prognostic reasons in patients with renal dysfunction. It may, however, exceed 24 h also in patients with normal renal function. As to the present knowledge, renal secretion does not contribute as a main pathway to PCT elimination.

Power and sample size in cost-effectiveness analysis.

For resource allocation under a constrained budget, optimal decision rules for mutually exclusive programs require that the treatment with the highest incremental cost-effectiveness ratio (ICER) below a willingness-to-pay (WTP) criterion be funded. This is equivalent to determining the treatment with the smallest net health cost. The designer of a cost-effectiveness study needs to select a sample size so that the power to reject the null hypothesis, the equality of the net health costs of two treatments, is high. A recently published formula derived under normal distribution theory overstates sample-size requirements. Using net health costs, the authors present simple methods for power analysis based on conventional normal and on nonparametric statistical theory.

Ratio-based and net benefit-based approaches to health care resource allocation: proofs of optimality and equivalence.

Both incremental cost-effectiveness ratios and net benefits have been proposed as summary measures for use in cost-effectiveness analyses. We present a unifying proof of the optimality and equivalence of ICER- and net benefit-based approaches to the health resource allocation problem, including both 'fixed budget' and 'fixed price' decision rules. If internally consistent willingness-to-pay values are used, ratio- and net benefit-based decision rules identify the same optimal allocation. Because they have identical resource allocation implications, use of one or other of the two approaches must be based on other criteria, such as their behaviour under conditions of uncertainty.

Comparison of procalcitonin (PCT) and C-reactive protein (CRP) plasma concentrations at different SOFA scores during the course of sepsis and MODS.

OBJECTIVES: The relation of procalcitonin (PCT) plasma concentrations compared with C-reactive protein (CRP) was analyzed in patients with different severity of multiple organ dysfunction syndrome (MODS) and systemic inflammation. PATIENTS AND METHODS: PCT, CRP, the sepsis-related organ failure assessment (SOFA) score, the Acute Physiology, Age, Chronic Health Evaluation (APACHE) II score and survival were evaluated in 40 patients with systemic inflammation and consecutive MODS over a period of 15 days. RESULTS: Higher SOFA score levels were associated with significantly higher PCT plasma concentrations (SOFA 7-12: PCT 2.62 ng/ml, SOFA 19-24: PCT 15.22 ng/ml) (median), whereas CRP was elevated irrespective of the scores observed (SOFT 7-12: CRP 131 mg/l, SOFT 19-24: CRP 135 mg/l). PCT of non-surviving patients was initially not different from that of survivors but significantly increased after the fourth day following onset of the disease, whereas CRP was not different between both groups throughout the whole observation period. CONCLUSIONS: Measurement of PCT concentrations during multiple organ dysfunction syndrome provides more information about the severity and the course of the disease than that of CRP. Regarding the strong association of PCT and the respective score systems in future studies we recommend evaluation also of the severity of inflammation and MODS when PCT concentrations were compared between different types of disease.

Postoperative plasma concentrations of procalcitonin after different types of surgery.

OBJECTIVE: Procalcitonin (PCT) and C-reactive protein (CRP) plasma concentrations were measured after different types of surgery to analyze a possible postoperative induction of procalcitonin (PCT), which might interfere with the diagnosis of bacterial infection or sepsis by PCT. DESIGN: PCT and CRP plasma levels as well as clinical symptoms of infection were prospectively registered preoperatively and 5 days postoperatively. SETTING: University hospital, in-patient postoperative care. PATIENTS: Hundred thirty patients were followed up; 117 patients with a normal postoperative course were statistically analyzed. INTERVENTIONS: None. MEASUREMENTS AND RESULTS: PCT concentrations were moderately increased above the normal range in 32 % of patients after minor and aseptic surgery, in 59 % after cardiac and thoracic surgery, and in 95 % of patients after surgery of the intestine. In patients with an abnormal postoperative course, PCT was increased in 12 of 13 patients. CRP was increased in almost all patients. CONCLUSIONS: Postoperative induction of PCT largely depends on the type of surgery. Intestinal surgery and major operations more often increase PCT, whereas it is normal in the majority of patients after minor and primarily aseptic surgery. PCT can thus be used postoperatively for diagnostic means only when the range of PCT concentrations during the normal course of a certain type of surgery is considered and concentrations are followed up.

Modulation of mouse endotoxin shock by inhibition of phosphatidylcholine-specific phospholipase C.

During Gram-negative bacterial infections, lipopolysaccharide (LPS) interacts with monocyte/macrophage receptors, resulting in a host defense response. Activation of intracellular signal transduction pathways implicating various protein kinase and phospholipases is crucial in activating the transcription of genes encoding proinflammatory cytokines and inducible nitric oxide synthase (iNOS). In this article, we demonstrate that in mouse, endotoxin shock activation of phosphatidylcholine-specific phospholipase C (PC-PLC) plays a major role in controlling the inflammatory response. Inhibition of PC-PLC by the specific inhibitor tricyclodecan-9-yl-xanthogenate (D609) before LPS reduced the release of interleukin-1 beta, interleukin-6 and nitric oxide (NO) in vivo. In contrast, tumor necrosis factor-alpha serum levels were not altered by the pretreatment with D609. Consequently, survival from endotoxin shock of D609-treated animals was significantly improved compared with control animals (45% vs. 20%). Thus, inhibition of PC-PLC can reduce the inflammatory response to LPS and may serve as a novel approach to therapy of sepsis.